DMP1 and DSPP in Osteogenesis and Dentinogenesis

描述（由申请人提供）：本研究计划基于非胶原细胞外基质（ECM）蛋白在骨生成和牙生成中起重要作用的总体假设。具体来说，我们关注的是牙本质基质蛋白1 （DMP1）和牙本质唾液磷蛋白（DSPP）的生物学功能。这两种蛋白在矿化组织形成中的重要性得到了大量基因研究的支持，这些研究表明，缺乏DMP1和DSPP编码基因的小鼠在骨和/或牙本质形成/矿化方面表现出缺陷。尽管这些研究表明这些蛋白质与健康矿化组织的形成之间存在关联，但DMP1和DSPP参与骨和牙本质形成的确切机制仍不清楚。DMP1蛋白水解形成N端（37 kDa）和c端（57 kDa）片段，DSPP蛋白水解形成DSP （N-端）和DPP （c -端）；这些碎片在骨和牙本质的外基质中大量存在。我们小组和其他人最近的发现使我们相信DMP1和DSPP的加工片段可能参与细胞信号传导和分化，除了它们在基质矿化中的直接作用。我们假设DMP1和DSPP的加工片段在细胞外基质矿化、细胞信号传导和细胞分化中起作用。为了验证这些假设，我们提出以下具体目标：具体目标1是研究DMP1， DSPP及其片段对生物矿化的影响。在这个特定的目的中，我们将研究这些蛋白质对成骨细胞和牙本质细胞矿化能力的影响。特异性目的2是研究DMP1、DSPP及其片段在牙本质形成和成骨过程中对细胞信号传导和分化的影响。总的来说，这些研究的数据将帮助我们更好地理解骨和牙本质形成的控制机制。获得F30奖学金是我实现特定目标的必要条件，也是我成为一名独立牙医科学家的必经之路。

DESCRIPTION (provided by applicant): This research proposal is based on the overall hypothesis that non-collagenous extracellular matrix (ECM) proteins play vital roles in osteogenesis and odontogenesis. Specifically, we are focusing upon the biological functions of dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP). The significance of these two proteins in the formation of mineralized tissues is supported by a number of gene studies showing that mice lacking the genes coding for DMP1 and DSPP display defects in bone and/or dentin formation/mineralization. Although these studies have shown the associations between these proteins and the formation of healthy mineralized tissues, the exact mechanisms, by which DMP1 and DSPP participate in the formation of bone and dentin, remain ill-defined. DMP1 is proteolytically processed to form the N-terminal (37 kDa) and C-terminal (57 kDa) fragments while DSPP is processed into DSP (N- terminal) and DPP (C-terminal); these fragments are present in significant quantity in the ECM of bone and dentin. Recent findings in our group and others have led us to believe that the processed fragments of DMP1 and DSPP may be involved in cell signaling and differentiation, in addition to their direct roles in matrix mineralization. We hypothesize that the processed fragments of DMP1 and DSPP function in extracellular matrix mineralization, cell signaling, and cell differentiation. To test these hypotheses, we propose the following specific aims: Specific Aim 1 is to examine the effects of DMP1, DSPP, and their fragments on biomineralization. In this specific aim, we will study the effects of these proteins on the mineralization capability of osteogenic and dentinogenic cells. Specific Aim 2 is to study the effects of DMP1, DSPP and their fragments on cell signaling and differentiation in dentinogenesis and osteogenesis. Collectively, data from these studies will help us better understand the controlling mechanisms involved in the formation of bone and dentin. Award of the F30 fellowship is necessary for me to fulfill the specific aims and to get training on my way towards becoming an independent dentist scientist.